Contribution of Malassezia towards ductal pancreas carcinoma

Pancreatic ductal adenocarcinoma (PDAC) represents the most common type of pancreatic cancer. In spite of all therapeutic progress, the 5-year-survival rate remains as poor as 6-20%. In view of the urgent need of new therapeutic approaches, this Austrian Science Fund (FWF) project intends to investigate how the yeast fungus Malassezia, which was found in pancreatic tumors, affects the progression of PDAC. In close collaboration with Assoc.Prof. Priv.Doz. Manuel Maglione (Department of Visceral, Transplant, and Thoracic Surgery) we will explore how Malassezia interacts with the cancerous cells themselves, but also with other cells forming the tumor environment. The gained knowledge will be used to obtain earlier tumor diagnosis, new fungus-specific therapeutic approaches and, finally, a better outcome for patients. The study is divided in three sub-projects. In each of them, various laboratory and cell culture methods as well as studies on patient-derived PDAC tissue samples will be applied. Furthermore, model systems will be used to simulate the complex situation in the living organism. In the first part, the interaction of Malassezia with the complement system as an important part of innate immune system and its effects on PDAC will be examined. The underlying hypothesis implies that Malassezia-driven activation of complement induces inflammatory processes that favor the progression of the tumor. Inhibitors of the complement system might therefore represent important therapeutic agents in the future. The second sub-project will explore the interplay of the yeast Malassezia with different cell types of the innate immune system, which are crucial for the defense against infections, but are also part of the tumor environment. We will focus on scavenger cells of innate immunity, but also on pancreas stellate cells, which show characteristics of both connective tissue cells and immune cells and therefore can strongly influence tumor growth. The third part of the project will deal with a group of fungal metabolites called bioactive indoles, which are generated and released by Malassezia. Some of these compounds are known for their capacity to induce proliferation of cancer cells. Most probably, these products also influence components of the immune system involved in tumor development, thereby affecting progression of PDAC. As a whole, this project will study the hypothesis that the migration of Malassezia yeasts from the intestine into the pancreas can result in progression of PDAC. The main aim is to identify the mechanisms of the fungal interplay with different elements of the tumor and the immune system that enable this process. This deeper knowledge will hopefully provide new possibilities for diagnosis and therapy of PDAC and help to improve the outcome of affected patients.